Methods of providing antioxidants to a drug containing product

ABSTRACT

A method of providing an antioxidant to a medical device and a kit are described.

CROSS REFERENCE

This application is a divisional application of U.S. application Ser.No. 11/189,216 filed on Jul. 25, 2005, now U.S. Pat. No. 7,785,647 theteaching of which is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

This invention generally relates to a method of providing a volatileantioxidant (e.g., butylated hydroxytoluene (BHT) and/or butylatedhydroxyanisole (BHA)) to a package with a medical device such as adrug-delivery stent.

Description of the Background

Drug delivery stent is becoming a common practice to treat, prevent orameliorate a cardiovascular condition or a related medical condition. Inmanufacture of drug coated stent, the drug or drug-polymer formulationis first applied onto the stent as a coating. The stent then undergoesmany post coating treatments, which may involve heat, moisture,pressure, sterilized gas, electron beam or radiation. After the stentsare packaged, it will face shelf life challenges. For example, if a drugis oxygen sensitive, oxidation degradation may occur during these steps.One of the commonly used methods to circumvent these shortcomings is toinclude one or more antioxidants in the stent coating formulation.Butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) arecommonly used antioxidant in food industry. For instance, many drugssuch as limus family (e.g. everolimus, sirolimus, ABT 578, biorolimus)and paclitaxel are oxygen sensitive. To preserve the drug integrity,antioxidant was introduced into the drug coating formulation. Among themare BHT and BHA.

BHA is a volatile solid with melting temperature of 45 to 63° C. BHT canbe sublimated at temperatures under its melting point (70° C.). Studieshave shown that in some stent coating processes, up to 40% BHT may belost during standard ethylene oxide (ETO) sterilization process, whichinvolves heat and moisture.

Therefore, there is a need for the preservation of BHT and/or BHA in astent manufacturing process. There is another need for the incorporationof BHT and/or BHA into the drug product.

The embodiments described below address the above described problems andneeds.

SUMMARY OF THE INVENTION

Provided herein is a method for providing a volatile antioxidant (e.g.,BHT and/or BHA) to a medical device (e.g., drug delivery stent) duringand/or after the manufacturing process of the device. The methodincludes adding an antioxidant (e.g., BHT and/or BHA) to a medicaldevice or a coating for the device, causing the antioxidant to permeateinto a medical device or a coating for the device, or otherwiseproviding an antioxidant in the proximity or surrounding of a medicaldevice (e.g., a stent). In some embodiments, the antioxidant permeatesinto a medical device or a coating of the medical device so as toprovide the antioxidant in the device and/or coating or to enhance thecontent of the antioxidant in the device and/or coating. The antioxidantcan be the same or different from the antioxidant in the device orcoating should the device or coating already include one.

The medical device can be a stent that can be a metallic or polymericstent which is biodegradable or nondegradable. The stent itself or acoating on the stent may include a bioactive agent such as paclitaxel,docetaxel, estradiol, nitric oxide donors, super oxide dismutases, superoxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), pimecrolimus,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, bioactive RGD, CD-34 antibody,abciximab (REOPRO), progenitor cell capturing antibody, prohealingdrugs, prodrugs thereof, co-drugs thereof, or a combination thereof.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows one embodiment of the present invention where anantioxidant is placed in a porous or permeable container in a productpackage containing a medical device;

FIG. 2 shows another embodiment of the present invention where anantioxidant is present between the product packaging that includes amedical device and a secondary packaging in that the antioxidant isplaced in the outer layer of the product packaging;

FIG. 3 shows another embodiment of the present invention where anantioxidant is present between the product packaging that includes amedical device and a secondary packaging in that the antioxidant isplaced in the inner layer of the secondary packaging;

FIG. 4 shows butylated hydroxytoluene (BHT) powder sublimation atdifferent temperature;

FIG. 5 shows BHT retained in a coating at different temperatures.

DETAILED DESCRIPTION

Provided herein is a method for providing an antioxidant (e.g., avolatile antioxidant), in some embodiments, butylated hydroxytoluene(BHT) and/or butylated hydroxyanisole (BHA), to a medical device such asa drug delivery stent or to a coating on the device during themanufacturing process or storage of the device. In some embodiments, themethod includes causing an antioxidant (e.g., BHT and/or BHA) topermeate into a medical device or a coating on the device or otherwiseproviding an antioxidant in the proximity of a medical device (e.g., astent) to allow the antioxidant to permeate into the medical device orthe coating of the medical device so as to provide the antioxidant tothe device or the coating or to enhance the content of the antioxidantin the device or the coating. The device or coating can include a drug.The antioxidant can be the same or different from the antioxidant in thedevice or coating should the device or the coating already include one.In some embodiments, the device or coating does not include anantioxidant such that the method provides for one to be added in thedevice or coating. In some other embodiments, the antioxidant added to amedical device or coating by the method described herein may compensatethe whole or part of the loss of the antioxidant in the medical device(e.g., stent) or coating during the manufacture or storage of themedical device. In one embodiment, the antioxidant is added to thedevice or coating in an amount more than the loss of the antioxidant inthe medical device or coating from the manufacturing process or duringstorage.

The medical device can be a stent that can be a metallic or polymerstent. The stent can be a biodegradable stent or a nondegradable stent.The stent may have a polymeric coating that may include a bioactiveagent such as everolimus. The coating can be biodegradable ornondegradable. In some embodiments, the stent, itself, can be apolymeric biodegradable, bioerodable or bioabsorbable stent, terms whichare used interchangeably unless specifically indicated, which caninclude the bioactive agent embedded in the body of the stent or coatingin the stent. The stent can be intended for neurovasculature, carotid,coronary, pulmonary, aorta, renal, biliary, iliac, femoral, popliteal,or other peripheral vasculature. The stent can be used to treat,prevent, or ameliorate a disorder such as atherosclerosis, thrombosis,restenosis, hemorrhage, vascular dissection or perforation, vascularaneurysm, vulnerable plaque, chronic total occlusion, claudication,anastomotic proliferation for vein and artificial grafts, bile ductobstruction, ureter obstruction, tumor obstruction, or combinationsthereof

Permeation of a Volatile Antioxidant into a Coating

In one embodiment, an amount (e.g., ranging from about 1 mg to about 10g) of a volatile antioxidant can be placed in a porous or permeablecontainer and then place the container inside a product package such asa Tyvek pouch within which a medical device (e.g., stent) is packaged.This embodiment is shown in FIG. 1, where the Tyvek package 100 containsa stent 110 and a porous or permeable container 120, which containsantioxidant 130. Thus, in one commercial embodiment, a kit is providedhaving a sterile device, such as a drug delivery stent, and anantioxidant included in the kit packaging. The stent can be packagedalone or may be pre-crimped on a delivery catheter or a ballooncatheter, ready for use by a health care provider. The figures do notillustrate a catheter assembly for delivery of the stent but suchdevices are well known to one having ordinary skill in the art. Forexample, permeation of BHT into a polymeric coating can be achieved byplacing a certain amount (e.g., 500 mg) of BHT in a porous or permeablecontainer and placing the container inside a Tyvek pouch within which amedical device such as a stent is packaged prior to ethylene oxide (ETO)sterilization. During the ETO process (typically at 55° C.), BHTsublimates to form a BHT gas. The BHT gas then fills in the Tyvek pouch.The permeation rate of molecules through a Tyvek pouch is sizesensitive. Larger molecules have a smaller permeation rate while smallermolecules have a larger permeation rate. Permeation rate of ETO, cresoland toluene on one kind of Tyvek material are listed below as examplesof molecular size dependence on the permeation rate (Table 1).

TABLE 1 Material Time to reach permeation rate of 1 μg/cm²/min) ETO 120Cresol 206 Toluene >480Since BHT is much more bulky than ethylene oxide, it is expected thatthe permeation rate for BHT is significantly lower than ethylene oxidegas. Depending on the type of Tyvek pouch, the permeation rate for ETOgas and moisture could be significantly different from the bulky BHTmolecule. Accordingly, over time, the Tyvek pouch can be over-saturatedwith BHT, which could reduce the escape of BHT from coated stents andeven may lead to reverse diffusion of BHT into a coating such as thecoating of a drug-delivery stent, increasing BHT content in the coatingof the stent. Should the coating not include an antioxidant, suchprocess may lead to the incorporation of the antioxidant into thecoating. In some embodiments, prior to the use of the device, the levelof antioxidant can be lower than the initial level of the antioxidant.In some embodiments, as mentioned previously, the level is higher. It isalso possible that the level of antioxidant is preserved, e.g., about±5%, about ±10%, about ±15%, about ±20%, or about ±30%.

In another embodiment, an amount (e.g., an amount from about 1 mg toabout 20 g) of an antioxidant or a volatile antioxidant (e.g., BHTand/or BHA) can be placed intimately close to a medical device, such asbioerodable polymeric stent or polymeric coated metallic stent, which ispackaged within a package (e.g., Tyvek package), in a gas impermeablesecondary package after sterilization. In some embodiments, it can bebefore sterilization. As shown in FIG. 2, the secondary packaging 200encloses a Tyvek packaging 210, which includes a stent 220. The kit caninclude the stent 220 by itself or pre-crimped on a delivery catheter orballoon catheter. On the outer layer of the Tyvek packaging 210, anantioxidant 230 is placed. The gas impermeable secondary package can bemade of any plastic or non-plastic material. In this embodiment, thevolatile antioxidant (e.g., BHT and/or BHA) evaporates over time, fillsthe space and prevents the infiltrated oxygen from damaging the product.To speed up the sublimation, one may optionally heat the entire finishedpackage to a temperature e.g., e.g., between 20° C. and, 70° C. (e.g.,about 30° C., about 40° C., about 50° C., or about 60° C.) for a shortperiod of time (e.g., about 10 seconds, about 20 seconds, about 30seconds, about 40 seconds, about 50 seconds, about 60 seconds, about 90seconds, or about 120 seconds) to allow enough antioxidant gas (e.g.,BHT gas) to fill the space of the secondary package. The heating can beachieved by any heating means known in the art. It is noteworthy that,in this embodiment, the volatile antioxidant (e.g., BHT) is not addeddirectly to the polymer and/or drug formulation.

In another embodiment, the shelf life of a medical device (e.g., stent)can be improved by providing a gas impermeable secondary package,placing (e.g., by coating) an amount (e.g., about 1 mg to about 20 g) ofan antioxidant (e.g., BHT particles or BHT film) in the inner-layer orinside of the secondary package, and placing a sterilized productpackage (e.g., Tyvek package) containing a drug-delivery stent that caninclude a antioxidant (e.g., BHA and/or BHT) into the secondary package.The sterilization can be by commonly known techniques including ETO. Insome embodiments, sterilization can be subsequent to placement in thesecondary package. As shown in FIG. 3, the secondary packaging 200encloses a Tyvek packaging 210, which includes a stent 220. On the innerlayer or inside of of the secondary packaging 200, an antioxidant 230 isplaced. The antioxidant will then evaporate to form a vapor whichprotects the enclosed product. The antioxidant can be the same ordifferent from the antioxidant in the medical device. As with any otherembodiments of the invention, such embodiment can be in the form of alabeled medical kit with a stent or the stent premounted on a deliveryor balloon catheter.

In a further embodiment, the product shelf life can be prolonged byplacing (e.g., by coating) an amount (e.g., about 1 mg to about 20 g) ofa volatile antioxidant (e.g., BHT particles or BHT film) on the outerlayer of a product package (e.g., Tyvek package) containing a medicaldevice (e.g., stent) that can include a antioxidant and placing theproduct package inside a gas impermeable secondary package. The medicaldevice can be sterilized prior to placement in the secondary package oralternatively after its placement. The antioxidant then evaporates overthe time to protect the drug from oxidation. It should be noted that theantioxidant can be added between the two packaging in solid, fluid orgas form and is not limited to a coating form. The antioxidant can bethe same or different from the antioxidant in the medical device shouldthe device already include one. Unless otherwise specifically indicated,the term “gas impermeable” means impermeable to an antioxidant gas,preferably to BHT or BHA (conversely, the term “permeable” meanspermeable to an antioxidant gas). Again, such an assembly can be in theform of a medical kit with a stent or the stent premounted on acatheter.

In a further embodiment, an antioxidant can be added to the formulationfrom which the device is made or from which the device is coated. Forexample, the antioxidant can be added to the polymer/solvent coatingformulation with or without a drug. The formulation could be used toform the reservoir layer or a topcoat layer on top of the reservoirlayer. The topcoat layer can be free of drug although in certaincircumstances some drug migration might occur.

The method described herein is applicable to any medical device coatedwith one or more drugs or bioactive agents with or without a polymericmaterial and optionally with one or more biobeneficial materials. Thedrug can be blended, conjugated, bonded or combined with a polymer. Themethod described herein is also applicable to any biodurable orbioabsorable (which can include bioerodable or biodegradable) deviceformed of a polymeric material optionally with one or more bioactiveagents. The drugs or agents can be compounded in the body of the deviceor coated on the device. The biocompatible polymer useful for forming acoating composition can be any biocompatible polymer known in the art,which can be biodegradable or nondegradable. Biodegradable is intendedto include bioabsorbable or bioerodable, unless otherwise specificallystated. Representative examples of polymers that can be used to coat amedical device in accordance with the present invention include, but arenot limited to, poly(ester amide), ethylene vinyl alcohol copolymer(commonly known by the generic name EVOH or by the trade name EVAL),poly(L-lactide), poly(D-lactide), poly(D,L-lactide),poly(D,L-lactide-co-L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide) (PDLLAGA),poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone),poly(hydroxyvalerate), polycaprolactone, poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-co-trimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly(aminoacids), polycyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), polyurethanes, polyphosphazenes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers, vinyl halide polymers andcopolymers, such as polyvinyl chloride, polyvinyl ethers, such aspolyvinyl methyl ether, polyvinylidene halides, fluoro polymers orcopolymers under the trade name Solef™ or Kynar™ such as polyvinylidenefluoride (PVDF) and poly(vinylidene fluoride-co-hexafluoropropylene),polyvinylidene chloride, poly(butyl methacrylate), polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics, such as polystyrene, polyvinylesters, such as polyvinyl acetate, copolymers of vinyl monomers witheach other and olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, isobutylene-styrene copolymers,methacrylate-styrene copolymer, ABS resins, and ethylene-vinyl acetatecopolymers, polyamides, such as Nylon 66 and polycaprolactam, alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers,polyvinylpyrrolidone (PVP), poly(vinyl alcohol) (PVA), polyacrylamide(PAAm), poly(glyceryl sebacate), polypropylene fumarate), epoxy resins,polyurethanes, rayon, rayon-triacetate, cellulose acetate, cellulosebutyrate, cellulose acetate butyrate, cellophane, cellulose nitrate,cellulose propionate, cellulose ethers, and carboxymethyl cellulose.

The biocompatible polymer can provide a controlled release of abioactive agent, if included in the coating and/or binding the bioactiveagent to a substrate, which can be the surface of a medical device or acoating thereon. Controlled release and delivery of bioactive agentusing a polymeric carrier has been extensively researched in the pastseveral decades (see, for example, Mathiowitz, Ed., Encyclopedia ofControlled Drug Delivery, C.H.I.P.S., 1999). For example, PLA based drugdelivery systems have provided controlled release of many therapeuticdrugs with various degrees of success (see, for example, U.S. Pat. No.5,581,387 to Labrie, et al.). The release rate of the bioactive agentcan be controlled by, for example, by selection of a particular type ofbiocompatible polymer which can provide a desired release profile of thebioactive agent. The release profile of the bioactive agent can befurther controlled by the molecular weight of the biocompatible polymerand/or the ratio of the biocompatible polymer over the bioactive agent.In the case of a biodegradable polymer, the release profile can also becontrolled by the degradation rate of the biodegradable polymer. One ofordinary skill in the art can readily select a carrier system using abiocompatible polymer to provide a controlled release of the bioactiveagent.

A preferred biocompatible polymer is a polyester, such as one ofpoly(ester amide), poly(D,L-lactide) (PDLLA), poly(D,L-lacticacid-co-glycolic acid) (PDLLGA), polyglycolic acid (PGA),polyhydroxyalkanoate (PHA), poly(3-hydroxybutyrate) (PHB),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly((3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanoate), poly(D,L-lactide),poly(L-lactide), polycaprolactone (PCL) and a combination thereof.

The biobeneficial material can be a polymeric material or non-polymericmaterial. The biobeneficial material is preferably flexible when presentas a discrete layer, or confers elastic properties in a blend orcopolymer, and is biocompatible and/or biodegradable, more preferablynon-toxic, non-antigenic and non-immunogenic. A biobeneficial materialis one which enhances the biocompatibility of a device by beingnon-fouling, hemocompatible, actively non-thrombogenic, oranti-inflammatory, all without depending on the release of apharmaceutically active agent. As used herein, the term non-fouling isdefined as preventing, delaying or reducing the amount of formation ofprotein build-up caused by the body's reaction to foreign material andcan be used interchangeably with the term “anti-fouling.”

Representative biobeneficial materials include, but are not limited to,polyethers such as poly(ethylene glycol), copoly(ether-esters) (e.g.PEO/PLA); polyalkylene oxides such as poly(ethylene oxide),polypropylene oxide), poly(ether ester), polyalkylene oxalates,polyphosphazenes, phosphoryl choline, choline, poly(aspirin), polymersand co-polymers of hydroxyl bearing monomers such as hydroxyethylmethacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),polystyrene-polyisoprene-polystyrene-co-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen,dextran, dextrin, hyaluronic acid, fragments and derivatives ofhyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, silicones, and combinations thereof. In someembodiments, the biobeneficial material can exclude any one of theaforementioned materials.

In a preferred embodiment, the biobeneficial material is a blockcopolymer comprising flexible poly(ethylene glycolterephthalate)/poly(butylenes terephthalate) (PEGT/PBT) segments(PolyActive™). These segments are biocompatible, non-toxic,non-antigenic and non-immunogenic. Previous studies have shown that thePolyActive™ top coat decreases the thrombosis and embolism formation onstents. PolyActive™ is generally expressed in the form of xPEGTyPBTz, inwhich x is the molecular weight of PEG, y is percentage of PEGT, and zis the percentage of PBT. A specific PolyActive™ polymer can havevarious ratios of the PEG, ranging from about 1% to about 99%, e.g.,about 10% to about 90%, about 20% to about 80%, about 30% to about 70%,about 40% to about 60% PEG. The PEG for forming PolyActive™ can have amolecular weight ranging from about 300 Daltons to about 100,000Daltons, e.g., about 300 Daltons, about 500 Daltons, about 1,000Daltons, about 5,000 Daltons, about 10,000 Daltons, about 20,000Daltons, or about 50,000 Daltons.

In another preferred embodiment, the biobeneficial material can be apolyether such as polyethhylene glycol (PEG) or polyalkylene oxide.

The bioactive agents can be any diagnostic, preventive and therapeuticagents. Examples of such agents include synthetic inorganic and organiccompounds, proteins and peptides, polysaccharides and other sugars,lipids, and DNA and RNA nucleic acid sequences having therapeutic,prophylactic or diagnostic activities. Nucleic acid sequences includegenes, antisense molecules which bind to complementary DNA to inhibittranscription, and ribozymes. Other examples of drugs includeantibodies, receptor ligands, and enzymes, adhesion peptides,oligosaccharides, blood clotting factors, inhibitors or clot dissolvingagents such as streptokinase and tissue plasminogen activator, antigensfor immunization, hormones and growth factors, oligonucleotides such asantisense oligonucleotides and ribozymes and retroviral vectors for usein gene therapy. Such agents can also include a prohealing drug thatimparts a benign neointimal response characterized by controlledproliferation of smooth muscle cells and controlled deposition ofextracellular matrix with complete luminal coverage by phenotypicallyfunctional (similar to uninjured, healthy intima) and morphologicallynormal (similar to uninjured, healthy intima) endothelial cells. Suchagents can also fall under the genus of antineoplastic, cytostatic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and antioxidantsubstances. Examples of such antineoplastics and/or antimitotics includepaclitaxel (e.g. TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.),docetaxel (e.g. Taxotere®, from Aventis S. A., Frankfurt, Germany)methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn,Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers SquibbCo., Stamford, Conn.). Examples of such antiplatelets, anticoagulants,antifibrin, and antithrombins include heparinoids, hirudin, recombinanthirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist, antibody, and thrombin inhibitors such as Angiomaxä (Biogen, Inc., Cambridge, Mass.). Examples of cytostatic agentsinclude angiopeptin, angiotensin converting enzyme inhibitors such ascaptopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co.,Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide®from Merck & Co., Inc., Whitehouse Station, N.J.), actinomycin D, orderivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 WestSaint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available fromMerck). Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁. Other drugs includecalcium channel blockers (such as nifedipine), colchicine, fibroblastgrowth factor (FGF) antagonists, fish oil (omega 3-fatty acid),histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, acholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc.,Whitehouse Station, N.J.), monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium.

Other therapeutic substances or agents which may be appropriate includealpha-interferon, genetically engineered epithelial cells, bioactiveRGD, antibodies such as CD-34 antibody, abciximab (REOPRO), andprogenitor cell capturing antibody, prohealing drugs that promotescontrolled proliferation of muscle cells with a normal andphysiologically benign composition and synthesis products, enzymes,antivirals, anticancer drugs, anticoagulant agents, free radicalscavengers, steroidal anti-inflammatory agents, non-steroidalanti-inflammatory agents, antibiotics, nitric oxide donors, super oxidedismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),dexamethasone, clobetasol, aspirin, estradiol, tacrolimus, rapamycin,rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),pimecrolimus, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), pimecrolimus, imatinibmesylate, midostaurin, progenitor cell capturing antibody, pro-drugsthereof, co-drugs thereof, and a combination thereof. The foregoingsubstances are listed by way of example and are not meant to belimiting. Other active agents which are currently available or that maybe developed in the future are equally applicable.

Examples of Medical Device

As used herein, a medical device may be any suitable medical substratethat can be implanted in a human or veterinary patient. Examples of suchmedical devices include self-expandable stents, balloon-expandablestents, stent-grafts, grafts (e.g., aortic grafts), artificial heartvalves, cerebrospinal fluid shunts, pacemaker electrodes, andendocardial leads (e.g., FINELINE and ENDOTAK, available from GuidantCorporation, Santa Clara, Calif.). The underlying structures can be ofvirtually any design. The device can be made of a metallic material oran alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108,cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or combinations thereof. “MP35N” and “MP20N” are trade namesfor alloys of cobalt, nickel, chromium and molybdenum available fromStandard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention. For example, the device can bea bioabsorbable stent, made from a polymeric material (and optionallyerodable metal). The bioabsorbable stent can include a drug coating, forexample with a polymer film layer or the drug can be compounded orembedded in the body of the stent.

Method of Use

A medical device (e.g., stent) having any of the above-describedfeatures is useful for a variety of medical procedures, including, byway of example, treatment of obstructions caused by tumors in bileducts, esophagus, trachea/bronchi and other biological passageways. Astent having the above-described coating is particularly useful fortreating occluded regions of blood vessels caused by abnormal orinappropriate migration and proliferation of smooth muscle cells,thrombosis, restenosis, and vulnerable plaque. Stents may be placed in awide array of blood vessels, both arteries and veins. Representativeexamples of sites include the iliac, renal, and coronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having with or without a drug delivery coating maythen be expanded at the desired area of treatment. A post-insertionangiogram may also be utilized to confirm appropriate positioning.

EXAMPLE Study of BHT Loss in the Stent Manufacture Process

Experiment Results and Discussion

Table 2 listed sampling schemes for the tested sample stents.

TABLE 2 Sampling scheme # of stent # of stent Stent for BHT for drugLabel Sampling steps test content 1 After stent secured on the balloon 54 and packaged in Tyvek pouch 2 After ETO sterilization 5 4Besides the sampling scheme for stents, BHT amount in the drug substanceand in the coating solution was also assayed. The stents weremanufactured by following standard Guidant procedures, which includeddrug coat solution mixing, spray coating, drying, stent retention on theballoon catheters, and packaging of coated stent device in Tvyek pouch.

Table 3 is a summary of BHT and total content of the drug (TC) testresults at the various stages of stent manufacture process.

TABLE 3 Summary of BHT and TC test results BHT found, % BHT GroupsConditions TC, % ng/ug drug retained % BHT loss Raw drug 1.78 100 0 Drugcoat 1.80 101.1 0 solution 1 before ETO 98.5 0.97 54.6 45.4 2 Post ETO94.8 0.11 5.9 94.1The percent BHT was normalized based on BHT in raw drug substance. Theresults showed that the drug mixing process did not change BHT content.About 45% BHT was lost during stent spray coating, drying and stentretention process. With conventional ETO process, BHT dropped from ˜50%to ˜5% before and after ETO. Total content recovery was correlated withBHT level. The higher the BHT amount in the stents, the higher the totalcontent recovery of the drug, indicating missing total content of thedrug might be related to oxidation of the drug.

Since BHT loss in ETO process was severe, a study was designed todetermine the cause. 100 mg of BHT was weighed in an aluminum pan andbaked in a convectional oven at 55° C. and checked at 1 hr and 16 hr.The pan was weighed after each time point. After overnight baking, allthe BHT powder was gone. The experiment was repeated at 70° C. for 30minutes and 1 hr. Since 70° C. is the melting temperature for BHT, theresults represented the worst case. The experiment was redone at 40° C.and 50° C. for 1 hr, 4 h, 7 h and 24 h. FIG. 4 is the plot of BHT weightloss vs. time at various temperatures. As shown in FIG. 4, it is clearthat BHT sublimation occurred at temperatures under 70° C. FIG. 5 is aplot of Ln (BHT/BHT₀) vs. time. Linearity was seen at 40° C. and 50° C.baking, indicating first order sublimation kinetics. No curve fittingwas performed on 55° C. and 70° C. experiment conditions, due to notenough data points. Equation 1 represents 1^(st) order kinetics,

$\begin{matrix}{{{Ln}\frac{BHT}{{BHT}_{0}}} = {- {kt}}} & (1)\end{matrix}$where BHT/BHT₀ is the ratio of BHT remained in the pan at time t and kis the sublimation rate constant at the experiment temperature. Usingequation 1, the half-lives for BHT sublimation are ˜13 hr at 40° C. and˜5 hr at 50° C.

Based on the curve fitting in FIG. 5, k_(40C)=0.048 and k_(50C)=0.1331.Using Arrhenius equation (Equation 2),

$\begin{matrix}{{{Ln}\frac{k_{2}}{k_{1}}} = {\frac{E_{a}}{R}\left\lbrack \frac{T_{2} - T_{1}}{T_{1}T_{2}} \right\rbrack}} & (2)\end{matrix}$where R is the gas constant (1.987) and E_(α) is the sublimationactivation energy, the activation energy for BHT sublimation is 20.5kcal/mol. The rate constant at other temperatures can be readilycalculated with equations 1 and 2.

The sublimation energy for BHT is about 2 times of water's heat ofvaporization, which is not very high. The experiment explained why BHTgot lost during ETO process. Long time exposure of stents at 55° C.during ETO process can cause sublimation of BHT. With polymerprotection, the sublimation rate was largely reduced.

The study showed that ETO process contributed heavily on BHT loss. Italso demonstrated the relationship between total content recovery andBHT levels on the stent. The study also demonstrated that one could takeadvantage of the volatile nature of BHT and BHA to enhance the productperformance by placing or coating BHT/BHA in the secondary package.Other benefits include increase in storage life of the product.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A kit, comprising: a pouch; a medical device witha drug in the pouch; a porous or permeable container in the pouch; andan antioxidant in the porous or permeable container such that themedical device with the drug is placed outside of the porous orpermeable container; wherein the antioxidant is a volatile antioxidantand evaporates and fills the space of the pouch.
 2. The kit according toclaim 1, wherein the antioxidant comprises butylated hydroxytoluene(BHT), butylated hydroxyanisole (BHA) or a combination thereof.
 3. Thekit according to claim 1, wherein the antioxidant is of a type tosublime to form a gas that permeates out from the container.
 4. The kitaccording to claim 1, wherein the antioxidant of claim 1 is a firstantioxidant; and wherein the medical device or the drug comprises asecond antioxidant, the second antioxidant being the same as ordifferent than the first antioxidant, such that the first antioxidant isadapted to be added to the medical device or the drug subsequent to aloss of the second antioxidant from the medical device or the drugduring the life of the medical device or the drug in the pouch.
 5. Thekit according to claim 1, wherein the medical device comprises a stent.6. The kit according to claim 1, wherein the medical device comprises acoated stent.
 7. The kit according to claim 1, wherein the coatingcomprises the drug.
 8. The kit according to claim 7, wherein the drug isselected from the group consisting of paclitaxel, docetaxel, estradiol,nitric oxide donors, super oxide dismutases, super oxide dismutasesmimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus), pimecrolimus,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), imatinib mesylate,midostaurin, clobetasol, bioactive RGD, CD-34 antibody, abciximab(REOPRO), progenitor cell capturing antibody, and prodrugs andcombinations thereof.
 9. The kit of claim 6, wherein the coated stent iscrimped on a delivery catheter or a balloon catheter.
 10. The kitaccording to claim 1, wherein the medical device comprises a coatingwhich comprises a biocompatible polymer.
 11. The kit according to claim10, wherein the biocompatible polymer is selected from the groupconsisting of poly(ester amide), ethylene vinyl alcohol copolymer,poly(D,L-lactide) (PDLLA), poly(D,L-lactic acid-co-glycolic acid)(PDLLGA), polyglycolic acid (PGA), polyhydroxyalkanoate (PHA),poly(3-hydroxybutyrate) (PHB),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanoate), poly(D,L-lactide),poly(L-lactide), polycaprolactone (PCL), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid-co-trimethylene carbonate), and acombination thereof.